The present invention generally relates to peptide-modified polyurethane compositions and methods of using such compositions. These compositions have improved properties that make them useful for a variety of applications, including, in particular, the manufacture of medical devices, articles, or implants that contact living tissues or bodily fluids.
Polyurethanes represent a major class of synthetic polymers that have been evaluated for use with a variety of medical implants. Polyurethanes have favorable mechanical properties (e.g., high tensile strength, tear and abrasion resistance, and stability in biological environments) and are generally biocompatible. Accordingly, polyurethanes are used with medical implants such as cardiac pacemakers, catheters, implantable prostheses, cardiac assist devices, heart valves, and vascular grafts. The favorable mechanical properties of some polyurethanes can be attributed to their two-phase morphology, which is derived from microphase separation of soft and hard polymer segments. The soft segment has a low glass transition temperature (Tg), and the hard segment has a high Tg. For polyurethanes used with certain medical implants, the soft segments may be formed from a polyether polyol such as polytetramethylene oxide (PTMO), and the hard segments may be derived from a diisocyanate such as 4,4′-methylenediphenyl diisocyanate (MDI) and a polyol chain extender such as 1,4-butanediol.
Vascular grafts are a type of medical implant in which synthetic polymers are useful. Certain vascular diseases often result in a need to open, replace, or bypass diseased or damaged blood vessel segments. In these situations, a graft may be used to direct blood flow around occluded segments of the vasculature, commonly referred to as bypass grafting. In coronary artery bypass grafting (CABG), occluded coronary arteries can be replaced with autologous tissue such as saphenous veins. But, some patients may not have suitable donor tissue, e.g., due to peripheral vascular disease or prior surgery, and a synthetic blood vessel substitute or graft may be required.
Synthetic polymers such as ePTFE (expanded polytetrafluoroethylene), Dacron (polyethylene teraphthalate), and microporous polyurethanes have been developed for use with synthetic grafts and other medical implants. In large-diameter (e.g., >6 mm) applications, these synthetic polymers have been successfully used as vascular grafts, but generally are not suitable for small-diameter applications such as CABG. In small-diameter applications, synthetic grafts often become occluded, decreasing the patency of the graft. Similarly, grafts with low blood flow are more susceptible to patency failure as compared to those in high blood flow. Thus, synthetic grafts are used infrequently for bypass or reconstructive procedures that require small diameters, such as the coronary artery and arteries below the knee.
Compliance also affects the function of small-diameter synthetic grafts. Vascular compliance is the ability of a blood vessel wall to expand and contract passively with changes in pressure and constitutes an important function of large arteries and veins. The compliance of a blood vessel generally is a structural property, which depends on the geometry (diameter and wall thickness) of the blood vessel, rather than a material property. To avoid discontinuity of blood-flow velocity, the compliance of a graft should match the compliance of the vessel it is replacing. Generally, smaller synthetic grafts are unable to meet the compliance requirements of small-diameter vessels.
Endothelialization of synthetic grafts may improve graft patency and improve a synthetic polymer's blood compatibility. Patency and compatibility, however, may be dependent on the attachment and retention (e.g., proliferation and migration) of endothelial cells on the graft or polymer surface. This dependency may be problematic since endothelial cells are known to detach upon exposure to physiological shear stresses. One way to adhere and retain endothelial cells on a synthetic polymer is to modify the polymer's surface. A number of surface modification strategies exist, such as attaching ionic groups, heparin, thrombomodulin, and growth factors to the graft or synthetic polymer. Another approach is to attach cell surface receptors and adhesion proteins (“adhesive peptides”), which are capable of mediating cell adhesion, to the surface of a synthetic material. For example, modifications of materials with adhesive peptides that promote integrin-mediated cell attachment, such as the RGD (arginine-glycine-aspartic acid) peptide, promote cell adhesion and spreading. RGD is known to interact with platelet integrin glycoprotein IIB/IIIA, so while RGD may enhance endothelial cell adhesion, it ultimately may decrease graft performance. The laminin-derived peptide YIGSR (tyrosine-isoleucine-glycine-serine-arginine), which binds nonintegrin receptors on endothelial cells, also may promote endothelialization when attached to synthetic polymers.
In general, the degradability of a synthetic material used with a medical implant should be considered. In some applications, degradable materials (e.g., poly(lactic acid)) are advantageous because they can be used for both tissue engineering and delivery of therapeutic agents to the implantation site. For example, cells may attach and grow on a degradable material, proliferate, and eventually adsorb and replace the material. These degradable materials are often degraded in vivo by hydrolysis or enzymatic mechanisms. To decrease thrombosis, degradable materials modified with adhesive peptides have been tested. For example, RGD has been attached to degradable block copolymers of biotinylated polyethylene glycol (PEG) with poly(lactic acid) (PLA) and poly(lactic acid-co-lysine).
The physiological response to a medical implant often includes platelet adhesion, platelet aggregation, and smooth muscle cell proliferation. In turn, this results in neointimal lesions at the implant placement site. Nitric oxide (NO) is a natural mediator of vascular homeostasis, and known to be a vasodilator, a regulator of vascular cell proliferation and migration, and an inhibitor of thrombus formation. NO has been shown to decrease the incidence of intimal hyperplasia in several animal models, and the inhibition of platelet adhesion and aggregation by NO and several NO-releasing materials has been reported. Synthetic materials that are capable of releasing NO may therefore be suitable for use with medical implants. However, the rate at which such materials release NO may be important. For example, if the release rate is too high, a dose of NO may cause a cytotoxic response, while too little may not stimulate endothelial cell proliferation to a desired degree or inadequately inhibit platelet adhesion and cell growth.